DESCRIPTION: (Applicant's Abstract) The discovery by Albert Hoffmann more than fifty years ago of the hallucinogenic effects of LSD irreversibly altered the course of both biological psychiatry and popular culture. Part of Hofmann's legacy is found in the August 1996 Advance Report of the National Household Survey on Drug Abuse which shows a dramatic increase in the use of hallucinogens among children 12-17 years of age; without question, the hallucinogens are drugs of abuse. But among the drugs of abuse, hallucinogens are perhaps unique in that an understanding of their mechanisms of action will not only ameliorate the burdens of illicit use but may also provide a key to solving the puzzle of psychosis, another major human affliction. The present investigations seek to characterize and to distinguish indoleamine hallucinogens such as LSD and phenethylamine hallucinogens as exemplified by DOM in combined behavioral [drug-induced stimulus control] and biochemical [radioligand binding and second messenger] studies. Specifically, the proposed experiments will identify the second messenger systems which mediate the discriminative stimulus effects of LSD and DOM and will, in addition, identify those serotonergic receptors which may modulate the effects of hallucinogens. These studies will also be extended to include the related indoleamine hallucinogens, 5-methoxy-DMT and ibogaine. Finally, the potentiation of LSD and other hallucinogens by fluoxetine and related selective serotonin reuptake inhibitors will be examined. Taken together, the use of powerful methods for the assessment of in vivo efficacy [drug discrimination], of in vitro efficacy [stimulation or suppression of second messenger formation], and of affinities for specific receptors [radioligand binding] will provide new understanding of the mode of action of hallucinogens.